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Sinecatechins 10% Ointment: A Green Tea

Extract for the Treatment of External Genital
Warts
Aditya K. Gupta, MD, PhD, FAAD, FRCPC; Deanne Daigle, MSc
Skin Therapy Letter. 2015;20(1)

Abstract and Introduction

Abstract

External genital warts (EGWs) resulting from the human papilloma virus (HPV) are a common
sexually transmitted infection and cause significant impairments in patient quality of life and
sexual well-being. Therapeutic options for EGWs can be providerassisted, but many patients opt
for treatment that can be applied at home. Sinecatechins 10% ointment is a new botanically
based patient-administered therapy for EGWs. It is comprised of >85% catechins, green tea
polyphenols that have been shown to possess antioxidant, antiproliferative, antiviral, and
antitumor properties. Phase III trials of sinecatechins 10% ointment have demonstrated higher
efficacy and lower recurrence rates compared to currently available patient-applied treatments.
Therefore, sinecatechins 10% ointment presents an alternative self-administered topical
treatment for EGWs.

Introduction

It is estimated that 1030% of the adult population in Canada is infected with human papilloma
virus (HPV).[1] While high-risk strains of HPV cause various types of cancer, low-risk strains can
cause condyloma acuminate, also known as external anogenital warts (EGWs). EGWs are highly
contagious and are, therefore, one of the most common forms of sexually transmitted infections.
The prevalence of EGWs in Canada is an estimated 1.8%, with an annual incidence rate of
154/100,000 for males and 120/100,000 for females.[2] Patients with EGWs present with one or
several cauliflower-like growths on the genitals and/or anal regions and clinical appearance is
often sufficient for a diagnosis. EGWs are associated with a significant burden of illness and
considerable impairment of patients' emotional and sexual well-being.[3] Although up to 50% of
untreated cases spontaneously regress at 6 months,[4] it is impossible to predict which lesions will
regress, remain unchanged, or proliferate;[5] therefore it is recommended that treatment be
offered to all patients with EGWs.

EGW treatment includes provider-assisted and patient-applied therapies or a combination of

these modalities. Treatment can be categorized as ablative, antiproliferative, or
immunomodulatory.[6] CO2 laser, trichloroacetic acid, excision, cryotherapy, and electrocautery
are ablative therapies that necessitate the assistance of a trained healthcare professional. Until
recently, patient-applied therapies were either antiproliferative or immunomodulatory in nature.
Podophyllin 1025% and podophyllotoxin 0.5% are patient-applied antiproliferative agents,
while imiquimod is an immunomodulatory agent that is available in both 5% and 3.75%
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formulations. Podophyllotoxin and imiquimod are considered the first choice among patient-
applied treatment options;[7] however, despite the greater ease and autonomy offered by patient-
applied therapy, clearance rates with these treatments are lower than those achieved with
physician-assisted options.[8] Furthermore, lesion reappearance is common regardless of
treatment choice as there is no way to eradicate the underlying viral infection.[6]

Sinecatechins ointment 10% (Veregen), a new patient-applied treatment formulated from green
tea (Camellia sinensis) extracts, has recently been licensed in Canada for the treatment of
EGWs.[9] Sinecatechins 10% ointment is comprised of >85% catechins, which are flavonoids
responsible for the antioxidant effects of green tea. Sinecatechins 10% ointment contains eight
different catechins, of which >55% is epigallocatechin-3-gallate (EGCG), the most abundant and
potent catechins.[10] Although the exact mechanisms of action of sinecatechins 10% ointment in
regression of EGWs are currently unknown, they are likely multimodal, consisting of antiviral,
pro-apoptotic and antiinflammatory responses.[11] The antiviral properties of EGCG may result
from the inhibition of activator protein 1 (AP-1) transcriptional activity that effectively down-
regulate expression of HPV genes. Transcription of anti-apoptotic HPV genes by the infected
cell could be counteracted by EGCG directly activating pro-apoptotic proteins as well as
upregulating and downregulating the expression of pro- and anti-apoptotic proteins, respectively,
resulting in cell death.[12] EGCG also possesses anti-inflammatory activity by inducing anti-
inflammatory interleukin (IL)-12 and reducing pro-inflammatory IL-10 activity. This would shift
towards a T helper cell type 1 (Th1)-mediated immune response promoting the elimination of
HPV-infected cells by the immune system. The various catechins and other molecular
constituents of sinecatechins ointment likely work synergistically to modulate these complex
biologic pathways to promote the regression of EGWs.[10] Therefore, although the exact
mechanisms of action of sinecatchins 10% ointment have not been fully elucidated, its efficacy
in treating EGWs may be attributable to its antioxidant, antiproliferative, antiviral, and antitumor
properties.[11]

Clinical Efficacy

Gross et al. conducted a Phase II/III, randomized, double-blind trial to assess the efficacy and
safety of two formulations of sinecatechins ointment for the treatment of EGW.[13] Two hundred
and forty-two participants (125 males, 117 females) with 230 warts (wart area of 12600 mm2)
were randomized to receive either sinecatechins 15% ointment, sinecatechins 10% cream, or
placebo (two placebo arms pooled for analyses). Participants were instructed to apply their
respective treatments three times a day for 12 weeks and those who achieved complete clearance
at the end of 12 weeks were followed for an additional 12 weeks. Rates of complete clearance of
baseline warts and of all warts (baseline and new) as well as recurrence rates for sinecatechins
10% cream and vehicle are displayed in . No significant differences between sinecatechins 10%
cream and placebo groups were found.
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Table 1. Efficacy rates for sinecatechins 10% ointment vs. vehicle

Phase II/III Phase III Pooled Analysis

Stockfleth et al.
Gross et al. 200713 Tatti et al. 200814 Tatti et al. 200916
200815
Sinecatechi Vehicl Sinecatechi Vehicl Sinecatechi Vehicl Sinecatechi Vehicl
ns 10% e ns 10% e ns 10% e ns 10% e
Cream (N=83 Ointment (N=10 Ointment (N=10 Ointment (N=20
(N=79) ) (N=199) 3) (N=202) 4) (N=401) 7)
Complete
clearance
of 46 37 51 39 55 34 - -
baseline
warts (%)
Complete
clearance
46 38 50 37 59 34 52 35
of all
warts (%)
Recurren
ce after
12 10 4 3 8 9 7 6
12 weeks
(%)

N = sample size

The efficacy of sinecatechins 10% ointment in the treatment of EGWs was further assessed in
two identically-designed, randomized, double-blind, Phase III trials,[14,15] the pooled results were
also reported.[16] A total of 1,005 participants (535 men and 470 women) with 230 EGWs and a
lesion area of 12600 mm[2] were allocated in a 2:2:1 ratio to receive sinecatechins 15%
ointment, sinecatechins 10% ointment or vehicle. Treatment was applied at 8-hour intervals three
times a day for 16 weeks or until complete resolution of all baseline warts was observed.
Complete responders were followed for an additional 12 weeks. Phase III trial results are
displayed in . Rates of complete clearance of all warts in both sinecatechins ointment groups
were significantly superior to vehicle (Ps<0.001). Time to complete clearance was also shorter
for participants treated with sinecatechins 15% and 10% ointment than those treated with vehicle
(P<0.01). Median time to complete wart clearance in the two trials was 16 weeks and 10 weeks
in the sinecatechins 15% and 10% ointment groups, respectively. In all studies, recurrence rates
were low and complete clearance rates were higher in women than in men.
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Table 1. Efficacy rates for sinecatechins 10% ointment vs. vehicle

Phase II/III Phase III Pooled Analysis

Stockfleth et al.
Gross et al. 200713 Tatti et al. 200814 Tatti et al. 200916
200815
Sinecatechi Vehicl Sinecatechi Vehicl Sinecatechi Vehicl Sinecatechi Vehicl
ns 10% e ns 10% e ns 10% e ns 10% e
Cream (N=83 Ointment (N=10 Ointment (N=10 Ointment (N=20
(N=79) ) (N=199) 3) (N=202) 4) (N=401) 7)
Complete
clearance
of 46 37 51 39 55 34 - -
baseline
warts (%)
Complete
clearance
46 38 50 37 59 34 52 35
of all
warts (%)
Recurren
ce after
12 10 4 3 8 9 7 6
12 weeks
(%)

N = sample size

Safety and Adverse Events

No serious adverse events (AEs) were reported in the Phase II/III study.[13] Only two participants
in the sinecatechins 10% group had AEs considered possibly or probably related to the study
drug and these included hyperkeratosis and skin discoloration. A number of local skin reactions
were reported, but no significant differences in severe local reactions between active treatment
groups and placebo were found. AE rates were also similar between treatment groups and
vehicle in the Phase III trials.[16] One patient in the sinecatechins 10% group developed severe
pustular vulvovaginitis, which was considered related to study drug.[14] Three patients in the
other Phase III trial developed moderate lymphadenitis, moderate rash, and moderate phimosis,
all were considered possibly related to the study medication.[15] The overall incidence of any
local reaction during treatment was higher in active treatment groups than vehicle (85.9% and
82.9% vs. 60.4%).[16] Incidence of most common application-site reactions are presented in . In
all studies, application-site reactions declined over the study period regardless of initial intensity.
It has been suggested that local reactions such as erythema are associated with the release of pro-
inflammatory cytokines; thus, patients should be advised that these signs may be indicative of
clinical response and are correlated with higher clearance rates.[15] Sinecatechins 10% ointment
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is contraindicated in individuals with a history of hypersensitivity to any of its components and

treatment should be discontinued if hypersensitivity occurs.

Table 2. Incidence of most common application-site reactions occurring in 5% of

participants11

Adverse Events Sinecatechins 10% Ointment (N=401) Vehicle (N=207)

Erythema 67.3% 32.4%
Pruritus 65.0% 45.4%
Irritation 63.5% 31.9%
Pain 46.5% 14.5%
Ulceration 46.0% 9.7%
Edema 39.8% 11.1%
Induration 27.3% 11.1%
Vesicles 18.8% 6.3%

Discussion

Sinecatechins 10% ointment was the first botanical drug approved by the US FDA and is now
available in Canada for the treatment of EGWs. Although provider-assisted therapies have higher
efficacy rates than patient-applied therapies, they are subject to the patient's pain tolerance and
aesthetic concerns, as some can cause considerable discomfort and/or result in scarring.
Provider-assisted therapies are also dependent upon the doctors' and patients' schedules and
patients may be hesitant to comply with repeat clinic visits because of the sensitive nature of this
condition. Consequently, many patients opt for more convenient treatment that can be self-
administered in the privacy and comfort of their home. Efficacy rates from the Phase III trials of
sinecatechins 10% ointment are higher than those achieved with podophyllotoxin 0.5% or
imiquimod 5% and 3.75%. However, it is recommended that sinecatechins 10% ointment be
applied three times a day in comparison to thrice weekly application with imiquimod 5% and
once daily application with imiquimod 3.75%. Therefore, patient adherence to the dosing
regimen may need to be considered, as compliance is an important factor in achieving treatment
effectiveness. Unlike other at-home treatments, it is not necessary to wash off the ointment prior
to the next application. Sinecatechins 10% ointment has lower recurrence rates relative to other
patient-applied therapies and is also the first EGW treatment to possess several disease-fighting
mechanisms, such as anti-inflammatory, antiviral, and antiproliferative properties. Therefore,
sinecatechins 10% ointment presents a botanically based alternative to currently available
treatments for EGWs that offers a satisfactory balance of clearance rates, reduced frequency of
lesion recurrence after successful treatment, and favorable adverse event profile.
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References

1. The Society of Obstetricians and Gynaecologists of Canada (SOGC). Incidence and

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of-hpv-in-canada/. Accessed November 24, 2014.
2. Kliewer EV, Demers AA, Elliott L, et al. Twenty-year trends in the incidence and
prevalence of diagnosed anogenital warts in Canada. Sex Transm Dis. 2009
Jun;36(6):3806.
3. Qi SZ, Wang SM, Shi JF, et al. Human papillomavirus-related psychosocial impact of
patients with genital warts in China: a hospital-based crosssectional study. BMC Public
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4. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human
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labs.com/our_products/Veregen-PM-En.pdf. Accessed November 24, 2014.
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